Right drug, right dose

Schizophrenia remains one of the most challenging brain disorders. Characterized by delusions and hallucinations, the illness disrupts cognition and emotion, profoundly affecting a person’s ability to think clearly and interact with others.

Imaging techniques, including PET and fMRI, are aiding understanding of the disease and the development of drugs to treat it.

The classic antipsychotic drugs, such as Thorazine, block receptors for the neurotransmitter dopamine, which also is centrally involved in Parkinson’s disease, addiction and other brain conditions. But while the drugs squelch the delusions and hallucinations, in high doses they also cause Parkinson’s-like symptoms, including rigidity and loss of muscle control, and they don’t improve cognitive function.

In the early 1990s, Herbert Y. Meltzer, M.D., and colleagues at Case Western Reserve University helped establish that clozapine and other second-generation “atypical” antipsychotics could effectively treat psychosis and improve cognition without Parkinsonism. This was great news, but how did the two classes of drugs produce such different effects?

This is where imaging came in.

Robert M. Kessler, M.D., and his colleagues at Vanderbilt had developed a number of radiolabeled compounds visible on PET scans that bound to a particular dopamine receptor, called D2, if it was not already occupied by an antipsychotic drug. In this way, the researchers could generate pictures of where in the brain the drugs were working.

Working with Meltzer, who currently directs the Division of Psychopharmacology at Vanderbilt, the researchers found that while the older drugs block D2 throughout the brain, the atypical class selectively binds to receptors in the cortex, the center of higher brain function, but not in areas involved in motor function.

“It’s a surprise nobody expected,” says Kessler, director of the Vanderbilt Center for Molecular Imaging. “It is the same receptor, the same protein” in both places.

The Vanderbilt researchers have also used fMRI to study the effect of drug treatment on specific cognitive functions, such as short-term working memory. By illuminating changes in blood flow and oxygenation, fMRI can create “pictures” of how the brain works under various treatment conditions.